Cited by 90Epigenetics and DNA MethylationPrenatal Substance Exposure EffectsNicotinic Acetylcholine Receptors Study

An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior

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Jung, Yonwoo, Hsieh, Lawrence S, Lee, Angela M, Zhou, Zhifeng, Coman, Daniel, Heath, Christopher J, Hyder, Fahmeed, Mineur, Yann S +4 more·2016·Nature Neuroscience

Abstract

Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.

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Authors
Jung, Y., Hsieh, L. S., Lee, A. M., Zhou, Z., Coman, D., Heath, C. J., Hyder, F., Mineur, Y. S., Yuan, Q., Goldman, D., Bordey, A., & Picciotto, M. R.
Affiliations
  • Yale University (US)
  • National Institute on Alcohol Abuse and Alcoholism (US)
  • The Open University (GB)
Corresponding author
Picciotto, Marina R
Venue
Nature Neuroscience
Published
2016-05-30
Volume
19
Issue
7
Pages
905-914
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2417118842
Cited by
90
References
50
Citations by year
2026: 5 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 15 · 2021: 9 · 2020: 11 · 2019: 9 · 2018: 7 · 2017: 9 · 2016: 6
FWCI
5.37
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Open Research Online - ORO (The Open University) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Institute of Mental Health (R01MH067528)
  • National Institute on Drug Abuse (R01DA014241, R29DA010455, R01DA010455, R37DA014241)
  • National Institute of General Medical Sciences (T32GM007205)
  • National Institute of Neurological Disorders and Stroke (R01NS086329, P30NS052519)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
epigenetics, ASH2L, MEF2C, histone methyltransferase complex, H3K4 trimethylation, dendritic complexity, cortical neurons, synapse maintenance, neuronal morphology
MeSH terms
Animals, DNA-Binding Proteins, Histones, Methylation, Mice, Inbred C57BL, Nicotine, Nuclear Proteins, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Transcription Factors, Epigenesis, Genetic

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